Liver disease is a major cause of infant and childhood morbidity and mortality. The diseases comprising pediatric liver diseases are individually rare, which has hindered the study of their causes/ pathophysiologies. As a result of this basic defect in understanding effective therapeutic strategies are lacking for most of them. This in turn results in many children with them progressing to end-stage liver disease necessitating orthotopic liver transplantation. Pediatric liver transplants comprise approximately 10% of all liver transplants performed, and the indications for most of them lie among the diseases to be studied in the Childhood Liver Disease Research and Education Network (ChiLDREN), the major objective of which is to combine the expertise and resources of the [Biliary Atresia Research Consortium] BARC and [Cholestatic Liver Consortium] CLiC clinical centers ... to study pediatric liver diseases. An essential element of this objective is the combined expertise of the participants, which serves to guide the study of the individual diseases included. A major objective of this application is to participate in ChiLDREN as an expert in genetically determined cholestasis (in particular progressive familial intrahepatic cholestasis) and in clinical aspects of infantile cholestatic liver disease in general. The other element of the major objective of ChiLDREN is the resources to be contributed by the clinical centers, the most important being the subjects with liver disease. Our center has been a leading contributor of subjects to both BARC and CLiC and expects to continue as such in ChiLDREN. By participating in these ways we expect to contribute substantially to the performance of ChiLDREN in achieving its goal of successfully eliminating pediatric liver disease as a major cause of infant and childhood morbidity and mortality. The specific aims at our center include: a) to participate fully as a clinical center in ChiLDREN; and b) to contribute to the understanding of the pathophysiology of progressive familial intrahepatic cholestasis by designing and implementing studies to be carried out by the membership of ChiLDREN. Relevance: Chronic pediatric liver disease, although rare, is a devastating condition that has high public health impact. Children with biliary atresia or any of the five genetic cholestatic liver diseases studied by ChiLDREN account for the majority of pediatric liver transplantations performed in the United States.